HPV is known to be a necessary cause of cervical cancer and a subset of other anogenital and head and neck cancers, including many cancers (e.g., cervical and anal cancers) that are elevated in the context of HIV. However, while HPV infection is common, development of cancer is rare. This suggests that in additional to HPV infection, co-factors are important for the development of cervical cancer. This project aims to elucidate the role of HPV and co-factors in the etiology of cervical cancer and its precursors, to define whether risk factors are similar or different for different histological forms of cervical cancer, and to apply knowledge gained to novel prevention strategies. Several studies have been conducted to date to achieve our goals, including a multicenter case-control study of cervical adenocarcinomas and squamous cell carcinomas in the US, a longitudinal study of women with low-grade, HPV-induced cervical lesions, and a cohort study of HPV and cervical cancer in Taiwan. Results from these studies to date have shown that 1) while HPV infection is required for the development of all histological types of cervical cancer the distribution of HPV types/variants observed in cancers vary by histology, 2) co-factors associated with distinct histological types of cervical cancer differ and while all histological forms of cervical cancer are associated with sexual behavior variables that predispose to HPV infection, cervical adenocarcinomas appear to be preferentially associated with risk factors that indicate hormonal involvement, 3) polymorphisms in immune-related genes (including HLA and KIR genes) are associated with the development of cervical cancer, and 4) HPV DNA testing is a useful screening test for the prevention of cervical cancer. In addition, we have conducted molecular epidemiology studies that have shown that 1) antibodies generated in response to natural infections protect against re-infection with HPV and 2) markers of mucosal immunity vary across the menstrual cycle and are affected by oral contraceptive use, suggesting that studies of local immunity and its role in predisposition to HPV persistence and progression need to account for these changes. This effort is sponsored by Intramural NCI funds.